title: CD44 splice isoform switching in human  and mouse epithelium is essential  for epithelial-mesenchymal transition  and breast cancer progression.
abstract: Epithelial-mesenchymal transition (EMT) is a tightly regulated process that is critical for embryogenesis but is abnormally activated during cancer metastasis and recurrence. Here we show that a switch in CD44 alternative splicing is required for EMT. Using both in vitro and in vivo systems, we have demonstrated a shift in CD44 expression from variant isoforms (CD44v) to the standard isoform (CD44s) during EMT. This isoform switch to CD44s was essential for cells to undergo EMT and was required for the formation of breast tumors that display EMT characteristics in mice. Mechanistically, the splicing factor epithelial splicing regulatory protein 1 (ESRP1) controlled the CD44 isoform switch and was critical for regulating the EMT phenotype. Additionally, the CD44s isoform activated Akt signaling, providing a mechanistic link to a key pathway that drives EMT. Finally, CD44s expression was upregulated in high-grade human breast tumors and was correlated with the level of the mesenchymal marker N-cadherin in these tumors. Together, our data suggest that regulation of CD44 alternative splicing causally contributes to EMT and breast cancer progression.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60614, USA.
authors.forename: Rhonda L
authors.initials: RL
authors.lastname: Brown
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Reinke
authors.forename: Marin S
authors.initials: MS
authors.lastname: Damerow
authors.forename: Denise
authors.initials: D
authors.lastname: Perez
authors.forename: Lewis A
authors.initials: LA
authors.lastname: Chodosh
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Chonghui
authors.initials: C
authors.lastname: Cheng
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D004848:Epithelium / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis* / Q000235:genetics*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D020033:Protein Isoforms
chemical_list: D015820:Cadherins; D018960:Hyaluronan Receptors; D020033:Protein Isoforms